13 Hypersensitivity Pneumonitis

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13 Hypersensitivity Pneumonitis

Michel William Brauner, Pierre-Yves Brillet, and François Guillon

M. W. Brauner, MD

Department of Radiology, UFR SMBH, Université Paris13 et Hôpi- tal Avicenne, 125 rue de Stalingrad, 93000 Bobigny Cedex, France P.-Y. Brillet, MD

Department of Radiology, UFR SMBH, Université Paris13 et Hôpi- tal Avicenne, 125 rue de Stalingrad, 93000 Bobigny Cedex, France F. Guillon, MD, PhD

Unité de Pathologies Professionnelles et Environnementales, UFR SMBH, Université Paris 13 et Hôpital Avicenne, 125 rue de Stalingrad, 93000 Bobigny Cedex, France

CONTENTS

13.1 Introduction 281 13.2 Pathogenesis 281 13.3 Pathology 282

13.4 Clinical Presentation 282 13.4.1 Symptoms 282

13.4.2 Physical Findings 283 13.5 Investigations 283 13.5.1 Blood Tests 283

13.5.2 Pulmonary Function Tests 283

13.5.3 Bronchoalveolar Lavage and Lung Biopsy 283 13.6 Diagnosis of HP 283

13.7 Specific Etiological Features 284 13.8 Etiology of HP 285

13.8.1 Microorganisms Contaminating Plants 285 13.8.2 Wood and Cork 285

13.8.3 Microorganisms in Laboratories 285 13.8.4 Contamination of the Workplace 285 13.8.5 Substances in Humid Environment 286

13.8.6 Contaminating Substances in Waste Processing and Storage 286

13.8.7 Production of Fertilizers and Compost (Table 13.4) 286 13.8.8 Contact with Antigenic Plant Dust 286

13.8.9 Animal Proteins 286 13.8.10 Chemical Hazards 286 13.8.11 Metallic Dusts 286 13.8.12 Metal Working Fluid 287 13.8.13 Detergents 287

13.8.14 Epoxy Resin 287 13.8.15 Acid Anhydride 287 13.9 Compensation 287

13.10 Occupational Differential Diagnosis 287 13.11 Imaging 287

13.11.1 Chest Radiography 287 13.11.2 Thin-Section CT 288

13.12 Treatment and Prognosis of HP 293 References 293

13.1 Introduction

Occupational lung disease comprises a wide variety of disorders caused by the inhalation of dust particles. Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis, is a world-wide, diffuse parenchymal lung disease characterized by an abnormal inflammatory immunological reaction to specific inhaled antigens contained in organic dusts. HP is caused by sensitization to repeated inhalation of organic dusts of plant or animal origin containing antigens or certain chemicals. Farmer’s lung (FL) (thermophilic actinomycetes) and bird fancier’s lung (BFL) (avian proteins) remain the most prevalent forms of the disease. HP is a complex disease of varying intensity, clinical presentation, and natural history. It is a serious disease, limited to the lung, that can lead to permanent lung dysfunction.

Although early phases are reversible, chronic HP leads to irreversible pulmonary fibrosis. All cases of HP have striking similarities among the clinical, pathological and radiological features, regardless of the specific exposure involved (Fraser et al. 1999).

13.2 Pathogenesis

The particles of biological dust are small, less than 5 +m in diameter. Deposition of smaller particles (1 +m or 2 +m) occurs predominantly in the distal air spaces of the lung. A large amount of particles is probably necessary.

HP is characterized by diffuse inflammation of lung parenchyma and airways. There is controversy regarding the mechanisms of the immune response.

Both humoral (type III) and cell-mediated (type IV) immune responses seem to play a role in pathogenesis (Salvaggio and Milhollon 1993). They are mediated by immune complexes and Th1 cells, respectively.

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Most patients have specific circulating antibodies (IgG and IgM precipitating antibodies to the antigen); however, approximately 10–50% of asymptomatic persons exposed to the sensitizing antigen also have these antibodies. The pathological response in the lung is probably mainly cell mediated resulting in alveolitis and granuloma formation. A variety of cells (macrophages, neutrophils, and lymphocytes) are involved in the pathogenesis. The alveolitis is neutrophilic at the beginning, then neutrophilic and lymphocytic, and latter lymphocytic. Proin- flammatory cytokines and chemokines activate alveolar macrophages, cause an influx of CD8+ lymphocytes into the lungs, facilitate granuloma formation, and promote the development of pulmonary fibrosis. Interferon (IFN)-gamma is essential for the development of HP, and interleukin (IL)-10 appears to modulate the severity of disease. Tumor necro- sis factor (TNF)-alpha and tumor growth factor (TGF)-beta have been implicated in development of the pulmonary fibrosis that is seen in chronic HP (Mohr 2004). If the exposure is prolonged, collagen deposition and destruction of the lung parenchyma occur.

13.3 Pathology

The different varieties of HP have similar histological features. In early disease, histological examination shows vasculitis. In the subacute stage of the disease, HP is characterized by alveolitis, bronchiolitis, and granuloma formation. Alveolitis consists of mononuclear cell infiltration of alveoli, alveolar wall, bronchioles, and similar interstitial cell infiltrate. Poorly defined non-caseating granulomas are also frequently observed. The lesions are usually diffuse but most severe in the peribronchiolar areas.

Bronchiolitis obliterans with intraluminal inflammatory polyps and organizing pneumonia are often seen in localized areas. Granulomas may progress to fibrosis. Chronic forms also reveal chronic interstitial inflammation and different degrees of fibrosis.

It may be mild and patchy, mainly in peribronchial areas or dense and diffuse with honeycombing.

Vourlekis et al. (2002) has reported six cases of HP in which the pathological characteristics of surgical lung biopsies met the criteria for non-specific interstitial pneumonitis (NSIP). HP should be included in the differential diagnosis of NSIP made by lung biopsy. Patients with the histopatho-

logical diagnosis of NSIP should be evaluated for possible HP.

13.4 Clinical Presentation

HP is a disease limited to the lung. Three different clinical presentations of HP have been described:

acute, subacute or intermittent, or chronic, accord- ing to duration of illness (Ashok et al. 2001). Con- tinual exposure may cause an overlapping of phases in the same patient (Remy-Jardin et al. 1993).

Recurrent episodes with infiltrative lung disease should raise the possibility of HP.

Intermittent exposure of susceptible individuals to a high concentration of antigens is accompanied by recurrent episodes of fever, chills, dry cough, and dyspnea, whereas continuous exposure to a lower concentration characteristically results in gradually progressive dyspnea in the absence of systemic symptoms (Fraser et al. 1999).

13.4.1 Symptoms

13.4.1.1 Acute Disease

Acute disease manifests as recurrent episodes. The symptoms appear 4–6 h following heavy exposure to an offending agent. The presentation is characterized by an acute pneumonitis-like illness with fever, chills, dry cough, chest tightness, dyspnea, headache, and malaise. Fine bibasilar crackles are often present. Sometimes, patients may develop acute respiratory failure. Systemic and respiratory symptoms often resolve spontaneously within 12–

48 h after cessation of exposure to the antigen.

13.4.1.2

Subacute Disease

Subacute disease manifests as recurrent “pneumonia” or as “chronic bronchitis” with an insidious onset occurring several days to weeks after exposure. Patients may gradually develop a chronic cough, sputum production, dyspnea, anorexia, and weight loss. The disease is insidious in onset and may occur over weeks. Improvement or complete

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recovery is often obtained if exposure terminated early; otherwise the disease may progress to interstitial fibrosis.

13.4.1.3 Chronic Disease

The chronic presentation is characterized by an insidious onset of productive cough, progressive dyspnea, fatigue, and weight loss. Removing exposure results in only partial improvement and patients may have irreversible lung damage.

13.4.2

Physical Findings

There are no specific findings of HP. Inspiratory basilar crackles or an inspiratory squawk (Earis et al. 1982) may be heard on examination of the chest.

Clubbing is observed in patients with long-standing hypoxemia and fibrotic disease.

13.5 Investigations

13.5.1 Blood Tests

No single blood test is specific for the diagnosis.

Leukocytosis with neutrophilia may be seen in acute disease. Elevated erythrocyte sedimentation rate, C- reactive protein level, and quantitative immunoglob- ulin level are often present. Precipitating immuno- globulin G antibodies against the suspected antigen confirms exposure but does not indicate active disease. It is only a marker of exposure. Many patients with clinical disease have no detectable antibodies (lack of appropriate antigen).

13.5.2

Pulmonary Function Tests

Pulmonary function tests reveal a restrictive pattern in early disease. In the acute phase, a reduc- tion in lung volume, carbon monoxide diffusing capacity, and static lung compliance are common.

Some patients also show evidence of small airway obstruction.

Pulmonary function tests can show restrictive, obstructive, or mixed defect in late disease. An airway obstruction is frequent in the subacute and chronic phase in combination with restrictive pattern.

In one study of long-term outcome of 33 non- smoking FL dating back at least 6 years (Lalan- cette et al. 1993), pulmonary function tests revealed an obstructive profile in 13 subjects, restrictive changes in 1, an isolated decrease in lung diffusion capacity in 3, and normal values in 16. Thin-section CT revealed emphysema in 9 of the patients who had airflow obstruction.

13.5.3

Bronchoalveolar Lavage and Lung Biopsy

A lymphocytic alveolitis is frequently observed (>20%) but non-specific. The proportion of sup- pressor cytotoxic cells (CD8 lymphocytes) is usually increased, and the CD4/CD8 ratio is usually decreased (less than 1) in the lung lymphocytes.

Higher levels of immunoglobulins IgG, TNF-_, and IL-6 may be detected in the bronchoalveolar lavage fluid. Abnormalities in this fluid may be found in asymptomatic individuals with antigen exposure.

Lung biopsy may be indicated in some cases, when the clinical diagnosis is difficult.

13.6 Diagnosis of HP

Although there is no single radiological, physiological, or immunological test specific for HP, the diagnosis can often be suspected on the basis of a compatible temporal relationship between pulmonary symptoms and a history of environmental or occupational exposure (Sharma and Fujimura 1995). The criteria required to make the diagnosis of HP are not clearly defined. However, it has been proposed to confirm HP in patients fulfilling four of the following major criteria and at least two of the following minor criteria (Schuyler and Cormier 1997).

Major criteria:

• Symptoms compatible with HP that appear or worsen within hours after antigen exposure

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• Conﬁ rmation of exposure to the offending agent by history, investigation of the environment, serum precipitin test, and/or bronchoalveolar lavage ﬂ uid antibody

• Compatible changes on chest radiography or computed tomography of the chest

• Bronchoalveolar lavage ﬂ uid lymphocytosis

• Compatible histological changes

• Positive natural changes or by controlled inhala- tional challenge

Minor criteria:

• Basilar crackles

• Decreased diffusion capacity

• Arterial hypoxemia, either at rest or with exer- cise

Lacasse and coworkers (2003) examined whether a clinical prediction rule might be reliable for making the diagnosis of HP without bronchoalveolar lavage or biopsy. They studied a cohort of 400 patients (116 patients with HP and 284 control subjects). HP was diagnosed on the basis of thin- section computed tomography (CT), bronchoalveolar lavage and, if necessary, surgical lung biopsy.

Six significant predictors of HP were identified: (1) exposure to a known offending antigen, (2) positive precipitating antibodies to the offending antigen, (3) recurrent episodes of symptoms, (4) inspiratory crackles, (5) symptoms occurring 4–8 h after exposure, and (6) weight loss. When all six factors were present, the probability of HP was 98%. The rule retained its accuracy when validated in a separate cohort of 261 patients. The authors conclude that the diagnosis of HP can often be made or rejected with confidence without bronchoalveolar lavage or biopsy, especially in areas of high or low prevalence.

The strongest single predictor of HP was exposure to a known inciting antigen.

13.7 Specific Etiological Features

Identifying exposure factors is essential for the diagnosis and treatment of HP. Circumstances of exposure, as for quantitative (antigen concentration, duration of exposure) or qualitative aspects (nature of antigen, period and frequency of exposure), are important to consider (Dalphin et al. 1999; Wild and Lopez 2001). History of exposure is a major

diagnostic tool which may be easily documented in the workplace. It may concern recurrent symptoms after renewal of the exposure, in the acute form of HP. However, those are not specific manifestations.

They are also described in the “organic dust toxic syndrome” (von Essen et al. 1990). In the subacute form, improvement after avoidance of the antigen is relevant evidence. This is sometimes difficult to observe, when the contact is continuous. The time of clinical diagnosis is also an appropriate feature, as most of the farmers take medical advice at the end of the winter, after the stabling period.

Chronic form is usually considered to be a sequelae state. It concerns either interstitial fibrosis with airway restrictive disorder or chronic obstructive pulmonary disease (COPD). In the case of farmer’s lung disease (FLD), development of COPD may concern half of the population (Braun et al. 1979;

Chaudemanche et al. 2003; Dalphin et al. 1993;

Erkinjuntti-Pekkanen et al. 1997). The existence of HP forms discovered only at the phase of chronic lesions (fibrosis or emphysema) is now admitted (Malinen et al. 2003). Thus, in the case of BFL, the only symptoms may be those of chronic bronchitis observed in 10% of cases (Bourque et al. 1989;

Depierre et al. 1988).

In chronic HP, the development of either fibrosis or emphysema seems to be related to the nature of exposure. Repeated exposure, as in FLD, seems to be associated with an increased risk of developing emphysema (Cormier et al. 2000; Erkinjuntti- Pekkanen et al. 1998). While continuous and unin- terrupted exposure, even at low-levels as in the case of BFL, leads mainly to fibrosis forms.

Exposure characteristics influence clinical features. Hence, proliferation of bronchoalveolar lavage lymphocytes exists in half of asymptomatic exposed subjects (Cormier et al. 1984), as well as for the presence of precipitating antibodies against the antigen (Prior et al. 2001; Roussel et al. 2004).

None of those biological findings has a prognostic value (Gariepy et al. 1989).

Using precipitating antibodies requires iden- tification of the exposure and information of the laboratory (Dalphin et al. 1994). A variety of detec- tion methods exist with different sensitivity and specificity. Their normalization is still incomplete (Aberer et al. 2001). The choice of the antigenic panel is therefore essential. Some laboratories are able to test sensitivity specifically against the suspected antigen. The knowledge of some regional antigenic particularities in the FLD may be useful for diagnosis (Roussel et al. 2004).

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A variety of antigens, some of them proper to a region, because of weather and/or local agricultural context has been associated with FLD (Table 13.1).

This is especially the case for grain workers, swine farmers, and hay packing, storage, and harvesting conditions.

Table 13.1. Antigen-inducing Farmer’s Lung Disease ( Dalphin et al. 1998)

Family Suspected antigen Thermophilic

actinomycetes

Micropolyspora faeni (Faenia rectivirgula) Thermoactinomyces (T.) vulgaris, sacchari, viridis

Streptomyces sp.

Micromycetes Aspergillus (A.) sp. (fumigatus, umbrosus) C. albicans

Penicillium brevicompactu and olivicolor Absidia corymbifera

Gram bacteria Erwinia herbicola Rhizopus sp.

Wallemia sebi Eurotium amstelodami

13.8 Etiology of HP

HP results from exposure to a variety of allergens and thus to related occupational exposure.

13.8.1

Microorganisms Contaminating Plants

Microorganisms contaminating plants concern mould spores or actinomycetes developing usually on rotting vegetable products. HP has been associated with thermophilic actinomycetes (T. vulgaris, T. sac- chari) growing in sugar cane (bagasse), malt (barley) (Aspergillus fumigatus or A. clavatus), paprika dust (Mocur stolonifa), pulp, and potatoes (thermophilic actinomycetes, Aspergillus). Dry sausage mould or

“sausage flower” may also be a source of contamination (Penicillium sp) (Marchisio et al. 1999;

Rouzaud et al. 2001). It is also the case with cheese dairy, mainly blue cheese and gruyere (Penicillium et Acarus siro). Esparto dust has been reported to induce stipatosis. Esparto grass (Stipa tenacissima) is a gramineous plant. Its fiber is used in Spain for the manufacturing of ropes, hemp sandals, rush mats, and also for decorative stucco plates used on walls and ceilings (A. fumigatus) (Hinojosa 2001).

13.8.2

Wood and Cork

Wood and cork often induce alveolitis because of their contamination by microorganisms (Table 13.2) (Halpin et al. 1994; Morell et al. 2003).

Table 13.2. Sources of antigen for wood (Dalphin et al. 1998) Source of antigen Probable antigen

Maple logs Cryptostroma corticale Sequoiosis Aureobasidium sp.

Graphium spp.

Oak and other wood Graphium spp.

Penicillium spp.

Paecilomyces sp. (varioti) Rhizopus spp.

Trichoderma koningii Alternaria

Cork Penicillium frequentans

Vine Botrytis cinerea

13.8.3

Microorganisms in Laboratories

Microorganisms in laboratories concern microbial and mycelial microorganisms encountered in research or clinical laboratories. In the chemical, pharmaceutical or biological industries, units of production of yeast, mould, or fungus may be source of contamination.

13.8.4

Contamination of the Workplace

Contamination of the workplace is mainly due to air conditioners and machine systems or humidifiers and dehumidifiers, encountered in the workplace or home environment (Table 13.3).

Table 13.3. Probable antigens causing hypersensitivity pneu- monitis in water-based systems (Dalphin et al. 1998) Thermophilic actinomycetes (M. faeni, T. vulgaris, candidus) Micromycetes: A. fumigatus, C. albicans, Alternaria, Fusari- um, Penicillium, Aureobasidium pullulans, Cephalosporium acremonium, Acanthamoeba

Bacteria: Bacillus subtilis, Pseudomonas sp., Cytophaga sp., Flavobacterium multivorum, Yersinia pseudotuberculosis, Aerobacterium liquefaciens, Klebsiella oxytoca

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13.8.5

Substances in Humid Environment

Mainly microorganisms, algae, mold developing in water or humid environment such as sauna water (Aureobasidium sp.), jacuzzi (Cladosporium clado- sporioides, Mycobacterium avium), sewers or swim- ming-pools.

13.8.6

Contaminating Substances in Waste Processing and Storage

In the industrial or domestic waste treatment plants, waste collectors are the most exposed to variety of dusts. Measures realized show high levels of microorganisms and vegetable or animal dusts, despite ventilation systems.

13.8.7

Production of Fertilizers and Compost (Table 13.4)

Table 13.4. Sources of antigen exposure in fertilizers and com- post (Dalphin et al. 1998)

Source of antigen Antigen

Fertilizers or manure Streptomyces albus Residential compost and

horticulture (wood chips for orchids)

Aspergillus sp.

Cryptostroma corticale

Moldy compost Thermophilic actinomycetes (M. faeni, T. vulgaris, Actinobi- fida dichotomica, Exellospora flexuosa, Thermomonospora alba, curvata, fusca) Micromycetes (A. glaucus)

13.8.8

Contact with Antigenic Plant Dust

Grain and flour have been associated with HP. It has been described in flour-mill workers because of contamination with wheat weevils (Sitophilus).

Tobacco leaves may also be contaminated (A.

fumigatus), as well as tea plants.

Mushrooms are themselves antigenic, mainly puffballs and their spores, those of pholiota (Pho- liota nameko), of Shiitake (Suzuki et al. 2001) or of pleurotus (Pleurotus florida).

Algae is another cause of HP either when in direct use (alginic acid) or with cyclohexane (1-3-bis isocy- anomethyl) for extraction of alginate from sea-weed for food-processing and cosmetic industries.

13.8.9

Animal Proteins

Avian antigens are the most frequently associated with the development of HP (pigeon breeder’s lung).

Many antigenic substances are concerned: feather bloom, avian serum (pigeons, chicken, turkey, goose, avian proteins), and excrement (mainly due to pigeon intestinal mucin). Continuous domestic exposure is an aggravating factor (Degracia et al. 1989). Also, contact with sea products is a source of HP: mollusk shell dust (Orriols et al. 1997), arthropod, cochi- neal. Animal furs are directly and indirectly a cause of contamination (furriers, taxidermists).

13.8.10

Chemical Hazards

Production of pyrethrum (insecticide made from the dried flower heads of chrysanthemums) is a source of HP.

Isocyanate vapors and aerosols in the plastic industry also induce HP. Those highly reactive low molecular weight substances are well documented as a cause of asthma and rhinitis. They are widely used in industry, mainly for production and use of plastic, lacquer, varnish, paint, polyurethane foam and in smelting works. HP has been associated with injec- tion molding operation (Merget et al. 2002; Simpson et al. 1996). However, few cases have been reported.

HP-like reaction has been investigated among workers using a resin (based on MDI) in a manufacture of wood-chip boards (Vandenplas et al. 1993) and in other isocyanate workers (Baur 1995).

13.8.11 Metallic Dusts

Zirconium, used in tile works and ceramics, may cause HP as may zinc vapors, mainly used by smelter workers.

Cadmium vapors are known to induce metal-fume fever and may lead to a characteristic pneumonitis (Barnhart and Rosenstock 1984). Their association with HP is not supported (Kelleher et al. 2000).

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13.8.12

Metal Working Fluid

In metalworking plants, microbial contaminated water-based metalworking fluid may be associated with HP (Pseudomonas fluorescens) (Bracker et al.

2003; Freeman et al. 1998; Gordon 2004).

13.8.13 Detergents

Production and use of detergents containing proteolytic enzymes of bacterial origin may be a source of HP due to inhalation of enzyme vapors (Bacillus subtilis) (Tripathi and Grammer 2001).

13.8.14 Epoxy Resin

Few reports have mentioned epoxy resins as being associated with HP but they contain solidifying agent and starting compound, especially acid anhydride (Piirilä et al. 1997).

13.8.15

Acid Anhydride

They are largely used in industry and chemistry and have been associated with asthma and HP ( Cartier et al. 1994; Czuppon et al. 1994; Gramer et al. 1994, 1998; Patterson et al. 1982; Zeiss et al.

1982, 1983).

13.9 Compensation

Compensation of HP is based on medical clinical features in association with the exposure to an identified antigenic substance at the workplace. In France, those criteria are specified via an executive order (INRS 2004). In the acute and subacute forms, clinical presentation should at least present clinical symptoms (dyspnea, cough, sputum production) with or without general signs (fever, weight loss) associated with disturbed spirometry and precipitating antibodies or lymphocytosis in bronchoalveolar lavage. In chronic HP, the contribution of chest CT scan is necessary.

13.10 Occupational Differential Diagnosis

Byssinosis is a bronchopathy due to inhalation of cotton dust, generally considered as an occupational asthma, although the immunological mechanism is still discussed. Respiratory syndrome induced by inhalation of nylon dust (Flock worker’s lung) is considered different from HP (Kern et al. 2000).

Metal fume fever following inhalation of metal fumes (zinc, copper) is an influenza-like reaction with poor respiratory symptoms different from HP.

13.11 Imaging

13.11.1

Chest Radiography

The different varieties of HP have quite similar radiological abnormalities regardless of the organic antigen responsible. The results of chest radiography are abnormal in most patients. It is a diffuse involvement of both lungs. Lymphadenopathy is rarely observed.

In the acute phase, chest radiography may be normal during an early phase, but most often shows diffuse or predominantly basal ill-defined air-space consolidation which reflects alveolar filling by various cells (Fig. 13.1). The air-space disease resolves

Fig. 13.1. Acute phase. Diffuse ill-deﬁ ned air-space consolida- tion

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in a few days, and fine nodules are then often visible on radiographs. Nevertheless, striated patchy opacities predispose to development of chronic changes (Monkare et al. 1985).

During the subacute phase, chest radiography most often shows a nodular or reticulonodular pattern (Fig. 13.2). The most frequent abnormalities are poorly defined small nodules (Fig. 13.3) and ground- glass opacities (Fig. 13.4). These small nodules reflect granulomas, cellular bronchiolitis, alveolitis and interstitial infiltrates. The abnormalities are most severe in the peribronchiolar areas. Even mild degrees of pulmonary involvement may cause severe

impairment of function because of the location of the granulomas within the respiratory bronchioles (Gurney 1992). The lesions involve mainly the middle and basal lung zones (Cook et al. 1988). In subacute HP, the radiographic abnormalities resolve within a few days or weeks after cessation of antigen exposure. In cases of continued exposure, a diffuse fibrosis appears.

In some cases, chest radiographs are normal, up to 33% in one study (Remy-Jardin et al. 1993) of BFL. On the contrary, chest radiographs may be abnormal without clinical symptoms.

In the chronic phase, chest radiography most often shows fibrotic changes with loss of lung volume (Fig. 13.5), coarse reticular opacities with sometimes overinflation (Fig. 13.6) of less affected areas, and emphysema. The fibrosis involves predominantly the middle lung zones or shows no zonal predominance.

Lung apices and bases are relatively spared (Adler et al. 1992). This topography of fibrosis is distinct to the subpleural, predominantly basal lesions of idiopathic pulmonary fibrosis and the upper and middle lung zones fibrosis of sarcoidosis. Fibrosis may develop months to years after the initial exposure.

13.11.2

Thin-Section CT

Thin-section CT is more sensitive than chest radiography and may reveal abnormalities in patients with normal chest radiographs (Remy-Jardin et al.

Fig. 13.2. Subacute phase. Reticulonodular pattern

Fig. 13.3. Subacute phase. Diffuse poorly deﬁ ned small nodules

Fig. 13.4. Subacute phase. Ground-glass opacity

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1993; Lynch et al. 1992). Thin-section CT can help to determine the specific diagnosis in patients with HP. In a study of 208 patients with various chronic interstitial lung diseases (CILD), including 13 subacute or chronic HP, a confident correct diagnosis was made by combining clinical and radiographic data in 6 and by adding the CT finding to clinical and radiographic data in 10 (Grenier et al. 1994).

Findings in acute HP typically consist of diffuse air-space consolidation. The consolidations may be diffuse or localized in the lower lung zones. Find- ings in subacute HP consist of patchy (Fig. 13.7 and 13.8) or diffuse (Fig. 13.9) areas of ground-glass

attenuation and small centrilobular nodular areas of hyperattenuation. On thin-section CT, the peribronchiolar granulomas result in poorly defined centrilobular nodules (Fig. 13.10) (Silver et al.

1989) and the alveolitis results in patchy or diffuse ground-glass opacities (Coleman and Colby 1988).

In the ground-glass pattern, the hazy increase in lung attenuation does not obscure underlying ves- sels. Ground-glass opacity is the main lesion in HP but also in other subacute or chronic infiltrative lung diseases: desquamative interstitial pneumonia, NSIP, and alveolar proteinosis. The patients with NSIP and alveolar proteinosis have ground-glass attenuation containing reticular opacities.

Sometimes HP has the pathological characteristics of NSIP (Fig. 13.11). The patients with desquamative interstitial pneumonia have often widespread ground-glass opacity indistinguishable from some cases of acute or subacute HP (Lynch et al. 1995).

Fig. 13.5.Chronic phase. Fibrotic linear opacities with loss of lung volume

Fig. 13.6. Chronic phase. Coarse reticular opacities with over- inﬂ ation

Fig. 13.7. Subacute phase. Patchy ground-glass opacity

Fig. 13.8. Subacute phase. Geographical ground-glass opacity with some lucent lobules

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and in other CILD: Langerhans cell histiocytosis, respiratory bronchiolitis, and lymphocytic interstitial pneumonitis, but the majority of patients with centrilobular nodules have HP; and, in the proper clinical context, the thin-section CT appearance is diagnostic if the nodules are correctly assessed (Gruden et al. 1999).

Fig. 13.9. Subacute phase. Diffuse ground-glass opacity

Fig. 13.10. Subacute phase. Poorly deﬁ ned centrilobular nodules

Fig. 13.11a,b. Hypersensitivity pneumonitis with the patholog- ical characteristics of non-speciﬁ c interstitial pneumonitis

Fig. 13.12. Subacute phase. Centrilobular nodules, the pleural and ﬁ ssural surfaces are spared

Fig. 13.13. Subacute phase. Diffuse ground-glass attenuation nodules

a

b

In the centrilobular pattern, the pleural and fis- sural surfaces are spared (Fig. 13.12). The nodules of ground-glass attenuation are diffuse (Fig. 13.13), and impacted airways are absent. There is a relationship between the nodules and the visible arterial branches, which are themselves centrilobular struc- tures. Centrilobular nodules may be observed in HP

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Focal areas of air-trapping on expiratory scans have been reported as common findings. Air-trapping has typically a lobular distribution (Fig. 13.14.a, b). It was observed in 86% of patients by Hansell et al. (1996). Small et al. (1996) reviewed thin-section CT scans in 20 patients with proven subacute HP, 12 of whom also had expiratory scans. On inspiratory scans, 18 patients demonstrated ground-glass opacification, and 14 showed a nodular pattern. Areas of decreased attenuation caused by small airways disease were visible in 15 of 20 patients on inspiratory scans; expiratory scans showed areas of air-trapping in 11 of 12 patients. In a series of 400 consecutive patients with infiltrative lung disease on inspiratory thin-section CT and expiratory images, 14 showed air-trapping on expiratory CT (Chung et al. 2001):

6 patients with HP, 5 patients with sarcoidosis, 2 patients with atypical pneumonia and 1 patient with pulmonary edema. In 8 cases, the inspiratory scans showed a combination of patchy or geographical areas of increased attenuation, decreased attenu-

ation, and normal-appearing lung resulting in an appearance that has been termed the “head cheese sign” because of its resemblance to the variegated appearance of a slice of sausage made from mixed meats (Chung et al. 2001).

Cystic spaces can be seen in a small proportion of patients with HP (13% in the series of 182 patients of Franquet et al. [2003]). The majority of cysts mea- sured less than 15 mm in diameter (Fig. 13.15). The nature of these cystic air spaces is uncertain. It may be that the cysts in HP result from partial bronchiolar obstruction by the peribronchiolar lymphocytic infiltrate. Franquet et al. (2003) concluded that ground-glass opacification, focal areas of air-trapping, centrilobular nodules, and cysts, when present, were highly suggestive of the diagnosis of subacute HP. Similar cysts have been reported in patients with lymphocytic interstitial pneumonia. The CT features of lymphocytic interstitial pneumonia are quite similar to subacute HP but the prevalence of lung cysts in subacute HP seems to be considerably lower than in lymphocytic interstitial pneumonia.

Lymphocytic interstitial pneumonia nearly always occurs in patients with underlying immunological abnormalities, most commonly Sjögren syndrome, multicentric Castleman disease and acquired immu- nodeficiency syndrome. It is easier to distinguish HP from other diseases having circumscribed air-containing spaces within the lungs, such as Langerhans cell histiocytosis and lymphangioleiomyomatosis (Brauner et al. 1989; Lenoir et al. 1990). Features distinguishing subacute HP from Langerhans cell histiocytosis include the presence of a background of diffuse ground-glass attenuation, ill-defined centrilobular nodules, and areas of air-trapping. HP can also be distinguished from lymphangioleiomyo-

Fig. 13.14. a Subacute phase. Ground-glass with focal lucent lobular and non-lobular areas b Subacute phase. Focal areas, mainly lobular, of air-trapping on expiratory scan

a

b

Fig. 13.15. Chronic phase. Fibrotic lesions with cystic spaces

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matosis by the presence of centrilobular nodules in the former (Franquet et al. 2003).

Chronic HP is characterized by the presence of fibrosis, although findings of active disease are often present (Remy-Jardin et al. 1993). Fibro- sis is characterized by lung distortion (Fig. 13.16) including irregular linear opacities, irregular interlobular septal thickening (Fig. 13.17) (Adler et al.

1992), honeycombing, and traction bronchiectasis (Figs. 13.18 and 13.19).

These abnormalities are often associated with poorly defined small nodules and areas of ground- glass opacities indicative of active disease (Fig. 13.20).

The fibrosis can be diffuse but usually involves mainly the middle or lower lung zones. Relative sparing of the lung bases usually allows distinction of this entity from idiopathic pulmonary fibrosis, in which the fibrosis

Fig. 13.20. Chronic phase. Reticulations and cysts associated with diffuse ground-glass opacity

Fig. 13.16. Chronic phase. Slight lung distortion with patchy areas of micronodules

Fig. 13.17. Chronic phase. Irregular linear opacities and ir- regular interlobular septal thickening

Fig. 13.18. Chronic phase. Honeycombing

Fig. 13.19. Chronic phase. Honeycombing with linear opacity.

Note a traction bronchiectasis in the middle lobe

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usually predominates in the lung bases (Lynch et al.

1995). Malinen et al. (2003) have compared thin-section CT findings of 88 long-term FL patients and 83 matched control farmers with a mean follow-up time of 14 years. Emphysematous, fibrotic, and miliary changes were recorded by means of thin-section CT.

Emphysema was found in 20 (23%) FL patients and in 6 (7%) controls (P=0.005). Emphysema in thin-section CT is more common in FL patients than matched control farmers, and the occurrence is increased by recur- rences of FL. Emphysematous, fibrous, and miliary changes in thin-section CTs of FL patients are multi- form and predominate in the lower parts of the lung.

Thin-section CT findings are often characteristic of HP, however identical findings may be seen in other interstitial lung diseases. Lynch et al. (1995) have compared 27 patients who had HP with 33 patients who had idiopathic pulmonary fibrosis. In 19 of the 27 patients with HP, the disease was chronic, while 8 had acute or subacute symptoms. All diagnoses were confirmed or supported by open lung biopsy. A CT diagnosis was made with a high level of confidence in 39 of 63 patients.

In these patients, the CT diagnosis was correct in 35 cases: 23 of 26 patients with a CT diagnosis of idiopathic pulmonary fibrosis and 12 of 13 patients with a CT diagnosis of HP. Of the 19 patients with chronic HP, only 7 had a definite diagnosis of HP based on CT findings. The patients with idiopathic pulmonary fibrosis were more likely than patients with chronic HP to have honeycombing and peripheral or lower lung zone predominance of disease. Thin-section CT can be used to distinguish idiopathic pulmonary fibrosis from HP in most cases. Chronic HP may have findings identical to those of usual interstitial pneumonia.

In conclusion, thin-section CT shows more abnormalities than chest radiographs and assesses better the distribution of lesions. In the subacute phase, the correct diagnosis is often easy using thin-section CT. Centrilobular nodules and areas of ground- glass opacities are reversible lesions. In the chronic phase, the diagnosis may be difficult using thin-section CT. The main lesions are architectural distortion, irregular linear opacities, and honeycombing.

They are irreversible (Webb et al. 2001).

13.12 Treatment and Prognosis of HP

In acute and subacute HP, the prognosis is good after cessation of antigen exposure. If the disease is not recognized at an early phase, fibrosis can develop.

Avoidance of organic antigen exposure is the most important factor in the management of HP.

Corticosteroids are indicated for the treatment of severe acute and subacute HP and for chronic HP that is severe or progressive. Long-term corticoste- roid therapy for the treatment of chronic HP should be considered only if objective improvement in clinical signs, pulmonary function, or radiographic abnormalities is documented (Mohr 2004).

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